Death from Nitrous Oxide

Nitrous oxide is an inflammable gas that gives no smell or taste. It has a history of abuse as long as its clinical use, and deaths, although rare, have been reported. We describe two cases of accidental deaths related to voluntary inhalation of nitrous oxide, both found dead with a gas mask covering the face. In an attempt to find an explanation to why the victims did not react properly to oncoming hypoxia, we performed experiments where a test person was allowed to breath in a closed system, with or without nitrous oxide added. Vital signs and gas concentrations as well as subjective symptoms were recorded. The experiments indicated that the explanation to the fact that neither of the descendents had reacted to oncoming hypoxia and hypercapnia was due to the inhalation of nitrous oxide. This study raises the question whether nitrous oxide really should be easily, commercially available.

KEYWORDS: forensic science, nitrous oxide, abuse, hypoxic asphyxia, death, restrictions Nitrous oxide is an inflammable gas that gives no smell or taste. Abuse of the gas is a problem with a history as long as its clinical use (1). A 1979 study revealed that up to 20% of medical and dental students in U.S.A. had used nitrous oxide in social settings to produce a "high" (2), and a 2003 study reported that 12% of the first-year students at Auckland University had used nitrous oxide for recreational purposes (3).
In clinical use, hypoxemia, diffusion into air-filled cavities, and interaction with B12-containing enzyme systems are wellknown side effects (4), and the risk to health professionals has been stressed (5). Symptoms related to B12 deficiency-related symptoms, such as myeloneuropathy (6), hyperpigmentation of the skin (7), and megaloblastic hematopoiesis (8), have also been described in relation to nitrous oxide abuse.
Deaths, although rare, have been reported by several authors. Brilliant (9) reported two deaths, one was a young person who filled a confined space and succumbed to asphyxiation, and the other person inhaled the gas through a tight-fitting mask apparatus which allowed no air to get in. DiMaio and Garriot (10) reported four deaths. In one case, nitrous oxide was inhaled directly from a gas tube. The other three deaths were caused when nitrous oxide was distributed into the car compartment where the three persons were sitting. Potocka-Banas et al. (11) reported a case, where a 32-year-old man died during inhalation of nitrous oxide from whipped cream cans using a face mask, thus under circumstances similar to our cases.
It is obvious that hypoxemia and hypercapnia may occur when breathing in a closed space, but we did not immediately understand whether, or how, nitrous oxide could alter the consciousness or the physiological response to this hypoxemia and hypercapnia. Thus, as rebreathing itself can be dangerous, we made a reconstruction to shed light over the actual fatal mechanism.

Case Report 1
The first case involves a 25-year-old, previously healthy industrial worker who was found dead in his home. He was lying on the floor in front of the TV set, which was switched on. The sweater was pulled up, the trousers and underwear were pulled down, and the face was covered by a modified gas mask (Fig. 1). The mask was connected to a rubber tube and a plastic bag, forming a closed system. A whipped cream pump was loaded with a nitrous oxide cartridge and connected to the plastic bag. Everything in the apartment was in good order, and there was no suicide note. The deceased had no history of any somatic or psychiatric disease and did not abuse alcohol or illicit drugs.
His girlfriend found the deceased when she returned home after the evening shift. She denied that he had expressed any suicidal thoughts or behaved in a depressed manner. Furthermore, she reported to the police that he earlier had bought nitrous oxide cartridges instead of carbon dioxide "by mistake" and soon thereafter he started to abuse the gas which was inhaled from the whipped cream nozzle or released into a plastic bag and subsequently inhaled. Often when he inhaled, he became warm and sweated profusely. She had also inhaled a few times but did not like the (side) effects. He had never made any attempt to hide his activities, and there were never, according to her, any sexual activities related to the breathing sessions. To her knowledge, this was the first time the mask was used. The mask was probably taken from the industry where he worked.
At autopsy, the areas covered by the gas mask were pale, sharply demarcated from cyanotic areas. Besides signs of congestion of the inner organs, there were no pathological findings.
Extensive microscopical analyses, analysis of alcohol, as well as screening for licit and illicit drugs, were all negative.

Case Report 2
The second case was that of a 35-year-old, previously healthy man, who was found dead on his living room floor. He was lying in front of the TV set and a VCR loaded with a pornographic videotape. His face was covered by a gas mask connected to a gas cylinder marked "N 2 O" (Fig. 2). He had no pants or underwear on, but was otherwise dressed, and four metallic pins were inserted in the penis and scrotum.
His girlfriend told investigators that the deceased had obtained the gas cylinder a couple of years earlier and that sometimes had used it in conjunction with sexual activities.
Except for minor puncture wounds in the genitals caused by the pins, there were no pathological findings at the autopsy. Extensive microscopical analyses, analysis of alcohol, as well as screening for licit and illicit drugs, were all negative.

Reconstruction of Case 1
A reconstruction was performed in an operation theater at the university hospital in order to examine the hazards of rebreathing in a closed space of small size and whether inhalation of nitrous oxide had any influence upon the individual's ability to experience dyspnea and/or other discomfort caused by hypoxia.
One of the authors (AE) volunteered and had food and fluid restrictions for 12 h prior to the experiments. An intravenous line was inserted for resuscitation purposes, the victim's modified gas mask was applied, and nitrous oxide was administered from the whipped cream can or from the wall nitrous oxide supply. One nitrous oxide cartridge contains c. 3.5 L of gas.
The concentration of N 2 O, CO 2 , and O 2 in the breathing circuit was continuously sampled and analyzed in a gas analyzer. The heart rate and the arterial hemoglobin O 2 saturation were measured using a pulse oximeter.
All data were continuously monitored on a display, not visible to the test person, and printed every 10 sec. Three different experiments were run with the same test person who was allowed to recover fully and to rest for at least 15 min between the different experiments. The test person was considered fully recovered when he subjectively felt recuperated and the vital signs were normal.

Experiment A
The plastic bag was filled with gas from one nitrous oxide cartridge and one expiratory tidal volume from the test person. The experiment was finished by the test person after c. 4.5 min when he felt discomfort and moderate dyspnea. The only subjective effect was a slight tingling feeling in the extremities. The peak N 2 O concentration was about 25% and leveled at c. 20% (Fig. 3a). At the end of the experiment, the arterial hemoglobin saturation was about 70%.

Experiment B
The conditions were the same as above, but no nitrous oxide was added. The experiment was stopped by the test person due to severe dyspnea after 3.5 min at an arterial hemoglobin saturation of about 80% (Fig. 3b).

Experiment C
The system was filled with nitrous oxide from the operation theater wall supply and intermittently refilled when the plastic bag collapsed. The peak nitrous oxide concentration was c. 50% and then oscillating between 40% and 50%. The experiment was stopped by the supervisors after 2.5 min when the arterial hemoglobin saturation fell to about 70% (Fig. 3c). There was no subjective dyspnea, instead the test person felt euphoria.
In none of the experiments did any sweating whatsoever occur. Tachypnea was seen in all experiments.

Discussion
As shown in the first experiment, only moderate dyspnea was felt even though the arterial O 2 hemoglobin saturation fell to about 70%, that is, almost to the level of the venous blood. When no N 2 O was administered in the breathing circuit, severe dyspnea occurred at a significantly higher O 2 saturation. In the third experiment, when N 2 O concentration in the inspired air was about 50%, no dyspnea was felt even though there was a rapid arterial O 2 desaturation. Thus, our experiment showed that 25% N 2 O in the inhaled air is sufficient to depress the sensation of dyspnea, and at higher N 2 O concentrations, the test person did not experience dyspnea.
In our first case, the concentration of N 2 O in the inspired air was probably somewhere between 25% and 50%, and in the second case probably even higher, because the gas mask was directly connected to the gas cylinder. Hence, it is likely that the two men succumbed to hypoxia without realizing the immediate danger.
In a situation with depressed or lost hypoxic response and with a rapid fall in O 2 concentration, it is very likely that hypoxia will occur with subsequent unconsciousness and cardiac arrest. In all experiments, there was a rise in end-tidal CO 2 to c. 8%. At these levels, the hypercapnia is expected to increase ventilation, as was seen in all experiments, but at higher concentrations, as would be expected if the experiment had proceeded further, the hypercapnia itself may have contributed to unconsciousness.
Obviously, serious and possibly fatal complications of this drug need to be more widely recognized by the medical community. Because of its potential danger, we believe that more effective control of the distribution and availability of this substance should be instituted.